Hepatocellular carcinoma (HCC) is a global healthcare challenge, which affects more than 815,000 new cases every year. Activated hepatic stellate cells (aHSCs) remain the principal cells that drive HCC onset and growth. aHSCs suppress the anti-tumor immune response through interaction with different immune cells. They also increase the deposition of the extracellular matrix proteins, challenging the reversion of fibrosis and increasing HCC growth and metastasis. Therapy for HCC was reported to activate HSCs, which could explain the low efficacy of current treatments. Conversely, recent studies aimed at the deactivation of HSCs show that they have been able to inhibit HCC growth. In this review article, we discuss the role of aHSCs in HCC pathophysiology and therapy. Finally, we provide suggestions for the experimental implementation of HSCs in HCC therapies.

In this retrospective study on 67 patients with hepatocellular carcinoma (HCC), after tumor resection, we evaluated the significance of CD3+ and CD8+ T-lymphocytes and CD20+ B-lymphocytes in tumor and non-tumor liver for time to recurrence (TTR), disease-free survival (DFS) and overall survival. After immunohistochemical staining, the density of nucleated lymphocyte profiles (Q_A) was estimated stereologically in the tumor center (TC), inner margin (inn M), outer margin (out M), peritumor and non-tumor liver. In TC, intermediate and high Q_A of CD8+ cells predicted longer TTR, whereas CD3+ and CD20+ were predictive only at high Q_A. DFS was predicted by high Q_A of CD3+, CD8+ and CD20+ cells in TC. The inn M harbored smaller Q_A of CD3+, CD8+ and CD20+ lymphocytes than out M. In contrast to out M, high T-cells’ Q_A and intermediate and high B-cell Q_A in inn M predicted longer TTR and DFS. High inn M/out M Q_A ratios of CD3+ and CD20+ cells were associated with longer TTR and DFS, whereas high inn M/out M Q_A ratio of CD8+ was predictive only for DFS. Patients with intermediate-high Q_A of combined CD8+ and CD20+ cells in inn M showed longer TTR and DFS, compared to CD8+-high or CD20+-high alone. Our findings highlight overall heterogeneity of the tumor invasive margin, the importance of inn M, and the predictive role of B-cells.

Purpose: Prognostic value of local B cells across nontumor colon mucosa (NM), primary colorectal cancer (pCRC), and its paired synchronous and metachronous liver metastases (LM) are currently under investigation. This retrospective, single-center, hypothesis-generating study aimed to characterize the spatial B cell distributions and their association with survival. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue sections from NM, pCRC, and synchronous ( N = 55) or metachronous ( N = 44) LM were stained immunohistochemically for B cells using anti-CD20 antibodies. Densities of B cells were assessed in NM, tumor center (TC), inner margin (IM), outer margin (OM), and peritumor area (PT) from pCRC and LM by using the QuPath software and assessed as prognostic variables for overall survival (OS). Results: Most B cells in NM were confined to mucosa-associated lymphoid aggregates (LAs), whereas the TC of pCRC showed significantly lower B cell density. In pCRC and LM, B cell–rich LAs were concentrated in the OM and PT but comprised less than 50% of the total B cell infiltrate. Higher B cell densities were observed in OM and PT vs. TC and IM of pCRC and LM in both groups. Higher B cell density was found in TC of pCRC vs. LM and in OM of LM vs. pCRC in both groups. High B cell densities in the entire PT region of pCRC and LM and in IM of LM, as well as scattered in the tissue, were associated with longer OS in synchronous group. High density of LAs themselves in pCRC and LM in the synchronous group was significantly associated with longer OS. Conclusions: High infiltration of both total and scattered B cells in pCRC and in synchronous LM correlated with improved OS. Further multicenter, prospective validation is required to determine its clinical utility.